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Purine nucleotides are competitive inhibitors of apo-GOT1

Pourmandi, N.; Jha, A.; Muzzarelli, K.; Lee, H.; Assar, Z.; Murray, G. J.; LaPointe, J. H.; Roddy, T. P.; Medeiros, G.; Sengupta, S.; Lyssiotis, C. A.

2025-09-17 molecular biology
10.1101/2025.09.17.676921 bioRxiv
Show abstract

The malate-aspartate shuttle (MAS) plays a key role in cellular metabolism by transferring electrons from cytosolic NADH into the mitochondrial matrix, thereby supporting oxidative phosphorylation, in addition to the citric acid cycle and amino acid metabolism. Here, we sought to identify allosteric regulatory metabolites of the MAS enzymes cytosolic glutamic-oxaloacetic transaminase 1 (GOT1) and mitochondrial GOT2. Using the Atavistik Metabolite Proprietary Screening platform, we identified several structurally similar metabolite hits-- most notably deoxyadenosine monophosphate (dAMP) and deoxyguanosine monophosphate (dGMP)--as candidate interactors with GOT1. Follow-up thermal shift assays revealed that dAMP and dGMP destabilize GOT1 in the absence of its cofactor, pyridoxal 5-phosphate (PLP), but have no destabilizing effect when PLP is present. Crystallographic analysis confirmed that dAMP and dGMP bind in the PLP pocket of GOT1, suggesting competitive binding. Together, these results indicate that nucleotide metabolites can interact with GOT1, offering potential insights into MAS regulation and therapeutic intervention strategies.

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